In contrast to the US and Europe, the pediatric HIV/AIDS epidemic in sub-Saharan Africa continues to expand. Perinatal HIV infection has a significant impact on brain development, and the achievement and maintenance of developmental milestones. Even though more than 80% of childhood HIV infections occur in Africa, the impact of HIV/AIDS on the health of African children remains poorly documented. No data exists on the impact of antiretroviral treatment on neurodevelopment in resource poor settings. The mechanisms of HIV neuroinvasion and neuropathogenesis over the course of infection remain largely unknown. Neurovirulent substrains may be responsible for the development of HIV-encephalopathy. The evolution of unique HIV lineages in the CNS has been shown to play a role in the development of HIV- associated dementia. No data are available on the potential role of HIV CNS compartmentalization in HIV encephalopathy in young children. We propose to conduct a prospective longitudinal community-based study to determine the first order (HIV exposure and infection) and second order (maternal AIDS and AIDS orphans) effects of the HIV epidemic on the neurodevelopment of young children in the Democratic Republic of Congo. We will also perform a cross- sectional characterization of HIV env compartmentalization in the CNS in HIV-infected infants (prior to initiating ART) to test the hypothesis that unique HIV env lineages are present in CNS versus peripheral compartments, and to provide insight into the pathogenesis of HIV-associated CNS disease in young children. Finally, we will perform a longitudinal characterization of HIV env CNS compartmentalization in children whose CNS manifestations do not reverse following ART. A better understanding of how HIV impacts neurodevelopment and causes encephalopathy in children would ultimately aid in the development of therapeutic strategies to prevent neurological complications experienced by children and adults alike.